Autism is the fastest growing developmental disorder in the United States with that affects about 1 in 68 children. Thus, not surprisingly, the cost and burden on families, patients, and caregivers is enormous. Associated with autism spectral disorder are other pervasive developmental disorders that include Rett syndrome, Phelan-McDermid syndrome and Fragile X syndrome. These ASD-associated syndromes are classified as rare genetic diseases and have limited or no treatment options. As such, there is an immediate need to develop more effective and better- tolerated medications for these patients. The overall goal of this Phase I SBIR is to further characterize and test the efficacy of our novel first-in-class pro-drugs that target the orphan Fragile X and Rett syndromes; with the long-term objective of improving the lives of individuals suffering from autism. Recently, a 12-week double- blind, placebo controlled treatment regimen of N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, resulted in a marked decrease in irritability in children with autism with few side effects. While the promise of NAC in autism is great, its ability to cross the blood- brain barrier is low. To address this, Promentis has developed several lead small molecules that successfully deliver NAC to the brain (far superior to NAC itself) and have further confirmed their preclinical proof-of-efficacy in rodent models of mental illness. Ultimately, NAC's early success in treating a major symptom of autism removes substantial risk from the project and increases the chances that Promentis will be successful in preclinical studies and subsequent Phase I clinical trials. We propose to conduct proof-of-efficacy experiments of our novel pro- drugs in rodent animal models of autism with the intention of developing a lead molecule to meet FDA requirements for IND filing.